It is possible to assess - and ameliorate -this aspect of living with HIV infection

Clinicians who treat patients with HIV disease have long accepted the notion that stress affects immune function. Indeed, this belief is nearly as old as the epidemic itself: counseling patients to reduce the number of stressors in their life has been standard advice since the days when the acquired immunodeficiency syndrome was known, variously, as GRID, ARC, and "gay cancer." Patients with the constellation of presenting symptoms that came to be known as AIDS-related complex-lymphadenopathy, candidiasis, herpes outbreaks, KS lesions, night sweats, fulminant fevers, unexplained weight loss, and a profoundly compromised immune system-were routinely instructed to avoid stress and strong sunlight, because both were believed to inhibit immune function.

As it turns out, this was good advice, even if it was based on very slim evidence. It remains good advice-and we now have scores of studies which show that stress has an invidious impact on immune function. More importantly, we now have studies which show that stress-reduction has a beneficial impact on immune function. In fact, the scientific discipline known as psycho-neuro-immunology has focused on this interrelationship since the mid-1960s. Much of the research in this field now focuses on people with HIV disease (1).

Over the past decade, research in this field has established that the immune system is directly influenced by psychological processes. Until these findings were published, the immune system was thought to be a completely autonomous body system, one responsive only to invading pathogens. The common belief was that the immune system regulates itself, that it is not influenced by other physiological systems, and that immunity is not influenced by psychological events. We now know that this picture is both incomplete and inaccurate.

What recent research has revealed is that the immune system is directly linked to the psyche by a complex network of nerves, hormones, and neuropeptides. This network of specific physiological pathways allows thoughts and emotions to have a direct impact on immune function and, consequently, on physical health (2).

We now know, for example, that profound psychological stress can suppress immune function and thereby accelerate disease progression in HIV-positive individuals. This is particularly true of what psychologists call sustained survival stress-which is defined by its duration (longer than four to six months) and by its nature (related to safety, security, or survival issues) (3). But how does a psychological state like sustained survival stress affect a biological process like immune function?

The belief that one's safety, security, or survival is threatened can trigger the so-called fight-or-flight response, which typically includes strong emotions of anxiety, fear, and anger. The mind focuses on the survival problem, the emotions become agitated, and a state of heightened physical and psychological arousal is maintained until some action or event diminishes the threat.

This heightened psychological state has specific effects on, and interactions with, the central nervous system, the autonomic nervous system, the endocrine-glandular-hormone system, and the immune system. When these systems respond to stress, heart rate accelerates, blood flow to muscles increases, and production of adrenaline and other powerful hormones rises. This last aspect of the body's response to stress has an immediate impact on appetite and immune function: both are suppressed. Appetite disappears as blood is diverted from the splanchnic bed to skeletal muscles, and the function of white blood cells is suppressed in order to maximize the flow of oxygen-carrying red blood cells (4).

The immunologic impact of sustained stress

These physiological responses to psychological stress are not harmful to the body over the short term. Indeed, most experts feel that a certain amount of short-term stress can even be beneficial to the body, similar to the effects of moderate physical exercise. However, sustained and unrelenting psychological stress-of the sort that qualifies, by its duration and nature, as sustained survival stress-does begin to take a toll on the body:

Sustained survival stress results in immune system inhibition, and eventually causes erosion of immune function

Intense, unremitting, unresolved grief can also weaken the immune system (Table 1). After a significant loss, grieving is natural, normal, and psychologically necessary to reestablish mental and emotional equilibrium. The grieving process typically lasts from three to six months; intense grieving that lasts substantially longer should be regarded as abnormal. Patients whose grief remains unresolved after six months or more should be strongly encouraged to seek the help of a professional counselor.

Table 1: Psychosocial Factors That Can Have a Negative Efect on Immune Function

All grieving has an impact on the immune system, and protracted, unresolved grief can be especially burdensome. Studies have shown that even the normal three-to-six-month grieving process impedes immune function to the extent that illness is more likely during the grieving period (5, 6). When researchers compared a group of HIV-positive men who had recently suffered the loss of a life-partner with a group of age-matched controls, they found that the immune systems of the bereaved men showed significant increases in neopterin levels and significant decreases in the immune proliferative response to PHA when that antigen was administered (7). The investigators noted that both of these changes are strongly associated with disease progression and the development of frank AIDS.

Other psychosocial factors that affect immune function

Survival stress and unresolved grief are but two of the many psychosocial factors that can have an adverse impact on immune function-and anything that compromises immune function is a matter of serious concern to those whose immune system is already severely compromised by the insidious effects of HIV infection. In the last five years, teams of investigators have identified a number of purely psychological factors that can have a negative impact on immune function and hasten disease progression. Among them are: a morbid fixation on death and dying as the inevitable outcome of HIV infection; clinical depression; absence of a sense of purpose in life, coupled with a lack of short- and long-term goals; an inability to assert oneself or to act decisively and effectively on one's own behalf; and poor coping skills in times of crisis (8-12).

Specific social factors can also have an impact, either positive or negative, on immune function and disease progression. In one recent study, a cohort of HIV-infected hemophiliacs was followed for a period of five years. Those reporting fewer intimate friendships showed a significantly more rapid deterioration in their CD4 counts (13). And when Solomon and colleagues studied a group of individuals with frank AIDS, they found that subjects who said they received considerable "problem-solving support" from friends and family were less likely to die than those who reported little support (14).

It should come as no surprise that gay men who conceal their sexual orientation progress to frank AIDS faster than those who are open about their affectional preference (15). Many stressors come into play here, of course, but a principal difference is that "closeted" homosexuals with HIV disease have practically no social support, whereas "out" homosexuals, especially those living in cities that have an active gay community, are buoyed by a social support system that includes everything from counseling services and "buddy" programs to legal aid and hot meals delivered to their door.

It should also come as no surprise that people with HIV disease who fail to take good care of themselves also experience a more rapid onset of AIDS. Patients who do not consume an adequate number of calories, who skip meals, or who fail to eat nutritionally balanced meals are at risk for AIDS wasting syndrome (see "Management of Wasting Syndrome in Late-Stage HIV Infection," Vol. 1, No. 5, pages 91-97). Recent research indicates that poor nutrition and diminished appetite can further suppress a seropositive individual's already suppressed immune system (16, 17). When HIV-positive patients do not sleep well, abuse alcohol and drugs, and/or get little or no vigorous physical exercise, immune function can be further eroded (18-20).

We now recognize that survival stress, grief, a morbid fixation on death and dying, clinical depression, and the absence of a sense of purpose are all independent risk factors for further suppression of immune function and for progression to frank AIDS. Researchers have measured the impact of each of these stressors on people with HIV disease (21, 22). But how can we assess the cumulative, compounding impact of all of these factors over many years? To live in an AIDS-afflicted community in the last decades of the twentieth century is to live in a world of unremitting grief and unabated survival stress. For gay men, for inner-city women of color, for hemophiliacs and IV-drug users, the loss of loved ones is not occasional, it is unrelenting-an unending cascade of loss and grief that often defies the best efforts of the strongest personalities to restore enthusiasm, optimism, and purpose to their lives.

Alleviating stress

What can clinicians and other care providers do to alleviate this situation? The first thing that all healthcare professionals can do is recognize that the stress of living with HIV can be reduced by means of specific interventions just as effectively as HIV viremia itself is now reduced by means of combination antiretroviral therapy. Take clinical depression, for example. It is a common response to HIV disease-and one of the most treatable. Yet depression often goes untreated in people with HIV, in part because providers fail to diagnose it, in part because patients themselves fail to recognize its manifestations (see "Depression and HIV Disease," Vol. 1, No. 6, pages 103-107).

There are several reasons for the frequency with which depression goes undiagnosed and untreated in people with HIV disease. For one thing, many of the classic symptoms of depression-fatigue, sleep disturbances, decreased libido, impaired concentration-are also common to symptomatic HIV disease itself. As a result, these symptoms are often incorrectly attributed to advancing infection rather than to depression.

Another reason that depression goes undiagnosed and untreated is that many caregivers incorrectly assume that global demoralization, a profound sense of hopelessness, and loss of direction, purpose, and self-esteem-all symptoms of depression-are normal emotional responses to the harsh realities of living with HIV. Given this pervasive belief, it cannot be stressed too often or too emphatically that chronic depression is never normal. Rather, depression is a constellation of physical symptoms and dysphoric moods that can be attributed, at least in part, to abnormal biological processes. Recognizing the symptoms of depression, and treating both the symptoms and their biological causes, will therefore benefit virtually all depressed individuals.

Pharmacotherapy is now standard treatment for clinical depression, and the advent of newer, safer, better-tolerated antidepressants has given providers many therapeutic options (Table 2). No specific agent or class of agents has been shown to be particularly effective in people with HIV disease, but all of the widely used antidepressants can be effective in these patients. A four-to-six-week trial will enable the practitioner to establish whether a given drug is effective in a given patient.

Healthcare providers should also recognize that all patients with clinical depression need regular counseling. While the primary care provider is in the best position to initiate this process, all depressed patients can benefit from the service of a therapist who is familiar with HIV disease. Standard, open-ended psychotherapy is generally inappropriate for these patients, whose time, energy, and finances may be limited.

We know that aggressive intervention, with a combination of pharmacotherapy and psychotherapy, can improve the outlook of depressed patients and relieve the sustained survival stress seen in people living with HIV. On a case-by-case basis, all those who provide continuing care to HIV-infected individuals have seen the positive results of such interventions. These successes led a number of researchers to wonder if a well-designed stress-reduction program, by reducing the stressors in these patients' lives, could boost immune function, reduce HIV-related symptoms, and improve longevity. The answer is an emphatic yes: we now know that such programs can increase immune function and improve the physical and mental health of HIV-positive individuals.

May cause sedation in a.m. at 150-300 mg when taken at night; 1/7000 incidence of priapism

Often used at doses of 25-50 mg in combination with other anti-depressants to treat sleep disturbance

A model stress-reduction program

Using what has been learned from studies of psycho-neuro-immunology, various groups have crafted programs designed to change behavior, enhance immunity, moderate symptoms, and increase longevity in people living with HIV. Model treatment programs for HIV-positive people now operate at the University of Miami's Center for Biopsychosocial Studies of AIDS, at the L.I.F.E. Program of the San Diego Lesbian & Gay Men's Community Center, and at Harvard Medical School's Mind/Body/Spirit Program for HIV/AIDS (see resources).

The L.I.F.E. Program, which I developed, is an acronym for Learning Immune Function Enhancement. This program teaches HIV-positive individuals how to assess their performance on 19 psychosocial cofactors that affect immunity and/or HIV disease progression (Table 1, page 28). Participants attend weekly group- counseling sessions for three months and then receive individual counseling on a weekly basis for an additional three months. Thereafter they are free to participate in a L.I.F.E.-run support group for as long as they want. The goal of the group and individual counseling sessions, and of the follow-up support program, is to enable L.I.F.E. participants to develop and implement strategies that will improve their performance in those psychosocial areas where weak performance puts them at risk (23).

Comprehensive treatment programs like the L.I.F.E. Program can have an appreciable impact on stress levels and health behaviors in participants who complete these courses. In our own program, roughly 70% of successful graduates report significant reductions in psychological distress and in behaviors that adversely affect immune function. About 60% of the graduates also report reductions in stress-related physical symptoms, chiefly gastrointestinal complaints (24). Recent research suggests that the successful management of these psychosocial factors can indeed change behavior, enhance immunity, moderate symptoms, and increase longevity in people living with HIV.